In the case of severe trauma and infection, the blood system is often affected. The coagulation system abnormalities and dysfunction are very common in the clinical manifestations of systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction syndrome (MODS). The blood system involvement in MODS ranks the top four in the organs involved in the literature reports and ranks the second in individual literature reports. The blood system abnormalities become the main cause and direct cause of the patents' death. The abnormal changes in the blood system during multiple organ dysfunction and failure are mainly divided into the changes in formed elements and the changes in coagulation and hemostatic functions. The coagulation dysfunction can be the inevitable result of disease occurrence and development and can also be induced by inappropriate treatment. In the case of massive hemorrhage caused by coagulation dysfunction in MODS, doctors are often helpless and most patients will die soon. Therefore, it is very important to research the key technologies for rescuing such dying patients.
Under normal circumstances, the coagulation process of organism is usually divided into intrinsic pathway, extrinsic pathway and common pathway.
The intrinsic coagulation pathway means that all the participatory coagulation factors come from the blood (intrinsic). When the vascular wall is injured, the subendothelial tissue is exposed and the negatively charged subendothelial collagenous fibers are in contact with the coagulation factors and combine with factor XII. factor XII is activated to become factor XIIa under the participation of HK and PK. Factor XIIa will activate factor XI without Ca2+ and the activated factor XIa will activate factor IX with the presence of Ca2+. Factor IXa itself activates factor X with fairly low effectiveness. As such, factor IXa shall be combined with factor VIIIa to form a 1:1 complex, also known as the factor X enzyme complex. Ca2+ and PL are required in this reaction jointly. The intrinsic coagulation pathway, in fact, refers to the process from the activation of factor XII to the activation of factor X.
The extrinsic coagulation pathway means that not all the participatory coagulation factors exist in the blood and there are extrinsic coagulation factors participating in hemostasis. This process is initiated by exposing of tissue factor to the blood, till the activation of factor X. As a specific transmembrane protein existing in a variety of plasma membranes, tissue factors is released after the tissue is damaged and forms a 1:1 complex with factor VII with the participation of Ca2+. Factor VII combined with the tissue factor will be soon activated by activated factor X to form VIIa. The extrinsic coagulation pathway is mainly adjusted by tissue factor pathway inhibitor (TFPI). TFPI is a kind of glycoprotein existing in normal human plasma, blood platelets and vascular endothelial cell. TFPI forms complex with factor Xa or factor VIIa-tissue factor-factor Xa to inhibit the activity of factor Xa or factor VIIa-tissue factor. In addition, studies have shown that intrinsic coagulation and extrinsic coagulation pathways can be activated mutually.
From the activation of factor X to the formation of fibrin is the common coagulation pathway of intrinsic and extrinsic coagulation, mainly including two stages including thrombin generation and fibrin formation.
(1) Thrombin generation: factor Xa and factor Va form prothrombin complex, i.e., thrombokinase in the presence of Ca2+ and phospholipid membranes. Thrombokinase transforms prothrombin into thrombin.
(2) Fibrin formation: fibrinogen is decomposed into fibrin monomers by the enzymolysis of thrombin and forms stable fibrin clot by cross-linking. This process can be divided into three stages, fibrin monomer generation, fibrin monomer polymerization and fibrin cross-linking. Hydrolyzing by thrombin, the negatively charged fibrinopeptide A and fibrinopeptide B are removed from fibrinogen to form fibrin monomers. After generation, the fibrin monomers are combined by non-covalent bonds to form fibrin polymer, also known as soluble fibrin. After generation, the fibrin can promote the activation of factor XIII by thrombin. With the involvement of XIIIa and Ca2+, the adjacent fibrins are cross-linked rapidly to form the insoluble stable fibrin clots.
Since pathogenesis of MODS has not been fully elucidated and no breakthrough has been made in regards to the clinical treatment of MODS, the fatality rate of MODS patients remains high, especially for patients with coma, emergency ulcer massive hemorrhage, etc. resulted from MODS, where traditional coagulation drugs can not play the role directly, and extracorporeal circulation adjuvant therapy at high cost are generally used to support the organs.
It is reported that four major coagulation factors (factor II, factor V, factor VII and factor VIII) in the coagulation system are synthesized by liver. Under MODS, the hyperbilirubinemia exists, aminotransferases (ALT or AST) rise, LDH rises, hypobilirubinemia exists, prothrombin time is prolonged, jaundice and flapping tremor exists; platelet count is less than 80000/μl or falls by over 50% in three days; arterial blood pressure ≦90 mmHg or the mean arterial blood pressure is ≦70 mmHg, accompanied with tachycardia, arrhythmia, cardiac arrest and so on. The existence of a variety of harmful free radicals aggravates the damages to the organs and especially brings series damage to liver, resulting in increased blood ammonia concentration, slow metabolism, blocked synthesis of key enzymes and important factors (4 major coagulation factors) and bringing life threat to the patients in massive hemorrhage under MODS.